Recent studies in models of cardiac ischemia/reperfusion injury have shown that a significant reduction in tissue damage from infarction can be achieved using MetaPhor's proprietary superoxide dismutase mimetics (SODm). In preliminary studies we found that M40403 a selective and potent SODm preserved cardiac function following ischemia/reperfusion injury. Based on the data that free radical generation, especially superoxide, may play a critical role in mediating tissue damage and death in heart following an ischemic event, such as a heart attack, we propose to develop a SODm mimetic of the M40403 class as a novel parenteral agent for administration after cardiac infarction or ischemia. M40403 will not be developed for this indication for reasons that are discussed in the proposal. Instead M40401, an SODm with higher catalytic activity, similar stability and improved toxicity to M40403 will be pursued. Given the enormous need for improving the outcome of cardiac ischemia and infarction, the novel findings of these SODm in protecting tissues from damage following ischemia/reperfusion injury, and the potential impact of this class of drugs on current management of heart disease in this country, we propose to move the program aggressively forward to clinical application and thus, are submitting this proposal for consideration. The Phase I application is focused on developing our mechanistic understanding of the role of superoxide in cardiac ischemia/reperfusion injury and to evaluate the effects of M40401 in protection against cardiac ischemia and to explore the potential use of this drug in post-ischemia management of heart disease. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE